4-fluoro-α-[2-methyl-1-oxopropyl]-γ-oxo-N-β-diphenylbenzene butane amide, the diketone, is a key intermediary in the preparation of atorvastatin. It had been witnessed that during the preparation of the diketone intermediate of atorvastatin, impurities such as desfluoro and difluoro are also formed. Elimination of the desfluoro diketone impurity poses problems during purification of atorvastain lactone.
WO 2003004457 discloses a new process for preparation diketone of atorvastatin by nucleophilic substitution of 2-bromo-1-(4-fluorophenyl)-2-phenylethanone with 4-methyl-3-oxopentanoic acid anilide in the presence of a base preferably metal hydroxide, carbonate, hydrogen carbonate in suitable solvents like methanol, ethanol, dioxane, tetrahydrofuran, dimethyl formamide, dimethyl acetamide, dimethyl sulfoxide, hexamethylphosphoric acid triamide and the like. This application describes the process of preparation of the above said intermediates from basic raw materials but does not disclose the control of impurities such as desfluoro diketone.
WO 2009/144736 A1 and U.S. Pat. No. 7,872,154 disclose the process for preparation of diketone of atorvastatin by reacting 2-halo-1-(4-fluorophenyl)-2-phenylethanone with 4-methyl-3-oxo-N-phenylpentamide in the presence of base such as sodium carbonate, potassium carbonate, cesium carbonate, diisopropylamine, triethylamine, metal hydroxide, sodium ethoxide, sodium hydride, n-butyl lithium, lithium diisopropylamide in C3-C5 alcohol as solvent. The patents identify the formation of O-alkylated impurity viz., 3-[2-(4-fluorophenyl)-2-oxo-1-phenyl-ethoxy]-4-methyl-pent-2-enoicacid phenylamide during the reaction and describes isolation methods to restrict its presence in diketone to less than 0.1%. The patent also describes the diketone of atorvastatin so obtained contains about 0.1% or less of desfluoro diketone and 0.05% or less of difluoro diketone. However, the patent does not disclose the methods for the preparation of starting materials and only describes that impurities are formed during nucleophilic substitution step.
Accordingly, there is a need for a process of synthesis for preparing 4-fluoro-α-[2-methyl-1-oxopropyl]-γ-oxo-N-β-diphenylbenzene butane amide wherein the impurities formed are either minimized or eliminated.